A program of studies will investigate the neurophysiological basis of noradrenergic actions in neuronal circuits in the central nervous system. The aim will be to establish a basis for the examination of the potential interactions between the noradrenergic system and three drugs of abuse: Amphetamine; cocaine and morphine. Function of the noradrenergic system will be examined in the cerebellum and cerebral cortex by employing microiontophoresis of drugs, stimulation of the locus corruleus, and physiological activation of somatosensory and visual afferent pathways. A new hypothesis will be explored which proposes that norepinephrine exerts a modulatory influence on synaptic efficacy in neuronal circuits. Specific studies on amphetamine will test for enhancement of noradrenergic synaptic function due to a combination of enhanced release of endogenous norepinephrine and direct agonist effects. Assays of noradrenergic NE action will also allow tests of the concept that cocaine in the central nervous system blocks norepinephrine release and reuptake processes. The improved criteria for identifying altered noradrenergic function will also be used to test whether morphine lowers tonic physiological noradrenergic activity by acting at terminals or within the locus coeruleus. Overall, the proposed research will contribute to a basic understanding of noradrenergic function, in parallel with tests to clarify the modes of action of drugs of abuse.